Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis of any malignancy. As no therapy over he past 50 years has substantially altered the median survival of 6 months, a paradigm shift is required to mprove outcomes. Through highly multidisciplinary studies, this proposal outlines an innovative strategy to reat PDAC using local image-guided delivery of multi-functional therapeutic nanoparticles (NPs). This ancreas-directed therapy, termed nanoembolization, involves intra-arterial (IA) delivery of molecularly argeted NPs directly into the blood supply of pancreatic tumors, followed by injection of embolic material to emporarily block blood flow. We will combine advanced interventional radiology catheter-based techniques with transcatheter intra-arterial perfusion magnetic resonance imaging (TRIP)-MRI, a method invented by the investigators to verify that tumors will be accurately targeted. Our motivation is to use a) NPs to penetrate the significant barrier of desmoplasia associated with PDAC and b) IA delivery to vastly increase the local uptake of NPs into tumors. IA delivery overcomes the non-target uptake of NPs into the reticuloendothelial ystem (RES) seen with intravenous (IV) injections. Although this project will initially test a therapeutic gold Au)-NP platform, it will provide a pipeline to test other submitted NP platforms. In Aim 1, we will synthesize ulti-functionalized NPs to target oncogenic KRAS, anti-apoptotic protein survivin, tumor-invasive etalloproteinase MT1-MMP (MMP-14), and to upregulate tumor suppressive microRNA let-7. NPs will be ested in human PDAC cell culture, using standard 2D culture and then embedded within a 3D collagenous atrix to mimic desmoplasia. For Aim 2, successful platforms will be submitted to the Nanotechnology Characterization Laboratory to verify safety. In Aim 3, non-toxic platforms will undergo efficacy studies in the Kras[12D] /P53[R172]/ Cre (KPC) mice, the definitive transgenic mouse model of PDAC. We will also assess whether changes in functional diffusion and perfusion MRI parameters can serve as early non-invasive biomarkers to predict survival. Aim 4 will optimize delivery of therapeutic NPs in the VX2 rabbit model of PDAC, originated by the investigators. In these rabbits, we will determine the benefits of nanoembolization to increase tumor uptake of NPs connpared to IV injections and IA delivery without embolization. This project will provide strong pre-clinical evidence of therapeutic benefit for nanoembolization in PDAC. In future early clinical trials, this novel local pancreas-directed therapy could be applied to patients alone or in combination with other systemic therapies.